Abstract

An appropriate balance between self-renewal and differentiation is crucial for stem cell function during both early development and tissue homeostasis throughout life. Recent evidence from both pluripotent embryonic and adult stem cell studies suggests that this balance is partly regulated by reactive oxygen species (ROS), which, in synchrony with metabolism, mediate the cellular redox state. In this Primer, we summarize what ROS are and how they are generated in the cell, as well as their downstream molecular targets. We then review recent findings that provide molecular insights into how ROS signaling can influence stem cell homeostasis and lineage commitment, and discuss the implications of this for reprogramming and stem cell ageing. We conclude that ROS signaling is an emerging key regulator of multiple stem cell populations.

ROS generation and scavenging. (A) Reactive oxygen species (ROS) include superoxide (O2.−), hydrogen peroxide (H2O2) and the highly reactive hydroxyl radical (OH.) (shown in red). O2.− can be generated from complexes I and III (shown in B) or through the oxidation of NADPH by NADPH oxidases. Subsequent reduction to H2O2 is catalyzed by superoxide dismutase (SOD). H2O2 can be further reduced to water (H2O) by catalase or can spontaneously oxidize iron (Fe2+) to form the highly reactive OH.. Under conditions of oxidative stress, when ROS generation outpaces the ROS scavenging system, accumulating levels of ROS oxidize and damage various cellular components. (B) The electron transport chain complexes I-IV harness electrons from NADH in a series of redox reactions, which are coupled to pumping protons (H+) into the mitochondrial intermembrane space. The proton motive force, a combination of the membrane potential (charge) and the concentration gradient (pH), powers ATP synthase (complex V). Normally, O2 acts as the final electron acceptor at complex IV, but aberrant reduction of O2 can occur at complexes I and III (red arrows), leading to the generation of O2.− (red).